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 Centre for Addictionand Mental Health |
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Research
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Molecular Neuroscience: Research Annual Report 2003Section Head: Dr. Hubert H.M. Van Tol The goal of the Molecular Neuroscience Section is to understand the mechanisms by which neural communication takes place. We seek to understand the molecular components involved in communication between neurons, how these components may contribute to mental illness and how they serve as therapeutic targets. The section has four principal investigators directing their own research groups. Dr. Hubert Van Tol is a University of Toronto Professor in the Departments of Psychiatry, Pharmacology and Institute of Medical Science, and Canadian Research Chair in Neurobiology (tier 1). Drs. Fang Liu and Albert Wong are University of Toronto Assistant Professors in the Department of Psychiatry, and Dr. Xian-Min Yu is an Assistant Professor at the University of Toronto Faculty of Dentistry. Our investigators use molecular, genetic, biochemical and electrophysiological approaches to study the molecules involved
in neuronal signalling. Our scientists mainly use in vitro approaches and model systems, including transgenic mice and the
nematode C. elegans, for their research. We collaborate with other scientists -- usually from the Neurogenetics Section at
CAMH -- to extend our findings to human disease. (http://www.uoftphysiology.com/neurosciencenet/governance.html) and outside Toronto; we are also members of the CIHR group The Synapse (http://www.utoronto.ca/synapse/). Molecular Neurobiology I This group focuses on the dopamine signalling system in the central nervous system. The dopamine signal-ling system is often considered the origin of, and/or one of the main targets for therapeutic intervention for, the symptoms of several psychiatric and neurological disorders, including schizophrenia, bipolar disorder, Huntington's disease, Parkinson's disease, Tourette's syndrome, addictions and attention-deficit/hyperactivity disorder. We hope to understand the individual components involved in the dopamine signalling system, so we can evaluate how the system contributes to development of disease, improve therapeutic interventions and minimize treatment side-effects. In our current research, we are trying to unravel the intracellular signalling pathways that mediate the effects of dopamine. Intracellular signalling cascades are initiated through the interaction of dopamine with a specific receptor on the plasma. In humans, five different dopamine receptors have been identified. These receptors mediate different physiological and biochemical effects, but are all members of the so-called G protein-coupled receptor (GPCR) family. New research by our group has revealed that these GPCRs, particularly the dopamine receptor subtypes that are targets for antipsychotic medication, can activate growth factor receptors, such as the platelet-derived growth factor receptor beta. Growth factor receptors are critical for the development, survival, differentiation and synaptic plasticity of neurons. This was a novel observation; however, we did not know its relevance in vivo. In collaboration with Dr. John F. MacDonald (Department of Physiology, University of Toronto), we found that transactivation is also critical for the mechanism by which dopamine receptors can reduce N-methyl-D-aspartate (NMDA) receptor activation in hippocampal and cortical neurons. We continue our studies to understand the mechanism by which dopamine receptors modulate NMDA receptor activity. The NMDA receptor is an ion channel that is activated by the major neurotransmitter glutamate, and it is known to be critically involved in synaptic plasticity, learning and memory and has been strongly implicated in psychosis. Our work identified a novel signalling cascade by which antipsychotic medication may modulate NMDA receptor signalling. G protein-activated inwardly rectifying K+ channels (GIRK; a.k.a. Kir3) are known effectors of dopamine receptors. These channels regulate the excitability of the cell and play an important role in the feedback regulation of dopamine release. We still do not know the precise nature of the channel-receptor relationship. We used molecular and biochemical approaches to show that the dopamine receptor and GIRK channel form a stable complex early during their synthesis. The observation that the receptor-channel complex is stable may help us understand how temporal control of synthesis of the individual components regulates GPCR-activation of different signalling pathways. We continue to investigate the molecular determinants of this interaction. Molecular Neurobiology II Our lab continues to focus on the molecular mechanisms by which G-protein coupled dopamine D! receptors exert functional cross-talk with NMDA receptors. Previously, we found that dopamine D1 receptors modulate NMDA glutamate receptor-mediated functions through a direct interaction of these two proteins. One interaction is involved in the inhibition of NMDA receptor-gated currents, and the other is implicated in the attenuation of NMDA receptor-mediated excitotoxicity. The D1receptor subtype is not a target for classic antipsychotic medication, but has been shown to play a role in working memory. This subtype is often thought to contribute to the "negative" symptoms of schizophrenia, which are not readily treated with classic antipsychotic medication. The NMDA receptor is one of the ligand-gated ion channels that is activated by the major excitatory neurotransmitter glutamate. Functionally, this ion channel is implicated in synaptic plasticity, learning and memory, but it also plays an important role in excitotoxicity and stroke. Psychotropic drugs like phencyclidine (PCP), that mimic schizophrenic symptoms, are known blockers of NMDA receptors. Furthermore, genetic disruption of the gene encoding this channel in mice results in animals that exhibit behaviour changes related to schizophrenia. Our ongoing study appears to be the first to provide the possible functional implications of inhibition of the NMDA -mediated cell death without jeopardizing NMDA -mediated excitatory neurotransmission, which is essential for maintaining the normal function of the central nervous system. Thus, the selective modulation of multiple NMDA receptor-mediated functions by direct interactions with D1 receptors may form a new avenue to identify specific targets for drug development to modulate NMDA receptor-governed synaptic plasticity, neuronal development and disease states. Molecular Physiology Our research focuses on the regulation and biophysics of the NMDA receptor, one of the ligand-gated ion channels activated
by the major excitatory neurotransmitter glutamate. As indicated above, this ion channel is implicated in synaptic plasticity,
learning and memory, excitotoxicity and stroke, and schizophrenia. Molecular Psychiatry Schizophrenia is a complex genetic disorder best reflected by a multiplicative multilocus model. Its complexity is a huge challenge for genetic studies, a challenge best met by using candidate gene analysis in family-based association studies. Candidate genes for these studies are mainly selected on the basis of their role in development or the functioning of the dopamine system or on the basis of being a target for drugs inducing psychosis. Current molecular technologies, particularly micro-array technologies, allow for the rapid screen of the expression of many genes. Our research aims to discover factors that contribute to the development of schizophrenia. Our main approach is to use rodent models for schizophrenia and post-mortem brain tissue of schizophrenia patients to identify genes that are altered in their expression and are consequently considered candidate genes underlying the disorder. Once identified, these candidate genes are further analyzed in human genetic studies. Genes with an altered expression in schizophrenia may be labelled as candidate disease genes. This approach led to the discovery of 14-3-3eta and syntaxin1a. Both these genes demonstrated a genetic association with schizophrenia. These genes affect the release of brain chemicals and are also involved in brain development. Now, our studies are looking into how these genes lead to schizophrenia. |
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Last updated: Aug 24, 2004 3:23 PM Published: Jul 01, 2011 5:57 AM ID#P5705 |